Atypical Metastasis of p16-Positive Tonsillar Squamous Cell Carcinoma to the Pleura: A Case Report
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PATHOLOGY
Atypical Metastasis of p16-Positive
Tonsillar Squamous Cell Carcinoma to
the Pleura: A Case Report
Claude Charles LeRose, DDS, MD,* and Carlos Antonio Ramirez, MD, DDSy
Incidence rates and patterns of distant metastases of head and neck malignancies are well documented in
the literature, such that focused management strategies are routinely practiced in anticipation of their
likely behavior. Head and neck tumors are known to most commonly metastasize to the lungs, skeletal
system, and liver, generally within 2 years of definitive treatment and in the context of poor locoregional
control of the primary lesion. Recent studies, however, have shown that human papillomavirus (HPV)–
positive oropharyngeal squamous cell carcinoma (SCCa) tumors display different patterns of distant me-
tastases than those traditionally described for head and neck HPV-negative SCCa tumors. This finding
has substantial implications for how patients undergoing treatment of these cancers should be surveilled
after therapy. This report describes a case of p16-positive tonsillar SCCa with metastasis to a highly unusual
secondary site in the pleura to show an example of the unconventional patterns of distant metastases
reported for HPV-positive oropharyngeal SCCa in the recent literature. We aim to provide a more thorough
understanding of this case by discussing the pathogenesis of metastatic spread to the pleura and the
clinical progression generally observed in patients with secondary pleural malignancy. This report goes
on to investigate how behaviors of distant metastases exhibited by HPV-positive oropharyngeal SCCa differ
from those of more conventionally described head and neck HPV-negative SCCa and the implications
thereof for strategies of post-treatment surveillance of these tumors going forward.
Ó 2018 American Association of Oral and Maxillofacial Surgeons
J Oral Maxillofac Surg -:1-5, 2018
Incidence rates and patterns of distant metastases of undergoing treatment of these cancers should be
head and neck malignancies are well documented in surveilled after therapy.
the literature, such that focused management strate- This report describes a case of p16-positive tonsillar
gies are routinely practiced in anticipation of their SCCa with metastasis to a highly unusual secondary
likely behavior. Head and neck tumors are known to site in the pleura to show an example of the unconven-
most commonly metastasize to the lungs, skeletal tional patterns of distant metastases reported for
system, and liver,1-3 generally within 2 years of HPV-positive oropharyngeal SCCa in the recent litera-
definitive treatment2,4 and in the context of poor ture. We aim to provide a more thorough understand-
locoregional control of the primary lesion.2 Recent ing of this case by discussing the pathogenesis of
studies, however, have shown that human papilloma- metastatic spread to the pleura and the clinical
virus (HPV)–positive oropharyngeal squamous cell progression generally observed in patients with
carcinoma (SCCa) tumors display different patterns secondary pleural malignancy. This report goes on to
of distant metastases than those traditionally described investigate how behaviors of distant metastases ex-
for head and neck HPV-negative SCCa tumors.4-7 This hibited by HPV-positive oropharyngeal SCCa differ
finding has substantial implications for how patients from those of more conventionally described head
Received from Department of Oral and Maxillofacial Surgery, Received May 24 2018
Ascension St John-Providence Health System, Detroit, MI. Accepted June 28 2018
*Resident. Ó 2018 American Association of Oral and Maxillofacial Surgeons
yProgram Director. 0278-2391/18/30769-9
Conflict of Interest Disclosures: None of the authors have any https://doi.org/10.1016/j.joms.2018.06.179
relevant financial relationship(s) with a commercial interest.
Address correspondence and reprint requests to Dr Ramirez:
Ascension St John Macomb-Oakland Hospital, 11900 E 12 Mile Rd,
Ste 210, Warren, MI 48093; e-mail: carlos.ramirez@ascension.org
1
2 ATYPICAL METASTASIS TO PLEURA
and neck HPV-negative SCCa and the implications for extracapsular spread. Eight days after neck dissec-
thereof for strategies of post-treatment surveillance tion, robotic radical resection of the right and left
of these tumors going forward. tonsils with inclusion of the right side of the base of
the tongue, retromolar trigone area, and pharyngeal
wall was performed. The tumor measured
Case Report 1.9 1.5 0.9 cm, with all resected margins histolog-
A 52-year-old man presented with a right tonsillar ically confirmed negative for malignancy. It was staged
lesion, confirmed by previous biopsy findings to be as pT1N2cMx.
p16-positive invasive SCCa, and clinically apparent The patient had an uncomplicated postoperative
lymphadenopathy in the ipsilateral neck. The use of course and underwent an appropriate course of adjunc-
p16 as a surrogate marker to identify HPV-positive tive chemotherapy and radiation therapy. Serial follow-
tumors in oropharyngeal specimens has been up examinations showed healing of the operative site
reported.8 Fluorine 18 fluorodeoxyglucose (FDG) within normal expected limits with no evidence of local
positron emission tomography (PET)–computed to- recurrence or regional lymphadenopathy. The findings
mography (CT) after biopsy showed the presence of of soft tissue neck CT and 18F-FDG PET-CT performed
a hypermetabolic mass on the right side of the 3 months after chemoradiation therapy were negative
oropharynx at the level of the right side of the base for locoregional disease recurrence or distant metastasis
of the tongue with 2 hypermetabolic lymph nodes (Fig 1).
measuring up to 1.7 1.0 cm representative of meta- The patient presented 11 months after treatment
static disease in the right carotid space. No evidence of complaining of progressive dyspnea with associated
abnormal uptake suggestive of metastasis was noted fatigue, generalized weakness, night sweats, anorexia,
within either lung field, the mediastinum, or any other and an unexplained 30-lb weight loss over the course
distant anatomic sites. of a single month. He appeared to have cachexia and
The patient’s surgical management was staged into dehydration and was noted to have decreased basilar
2 procedures. Bilateral selective neck dissections of breath sounds bilaterally. Abdomen-chest CT showed
levels 2 to 5 were performed first, confirming the pres- bilateral pleural effusions with diameters measuring
ence of metastatic carcinoma in 4 nodes of the ipsilat- up to 4.3 cm in the left and 2.3 cm in the right pleural
eral neck (3 nodes at level 2A and 1 node at level 4) and spaces, as well as consolidation at both posterior lung
1 node of the contralateral neck (level 2A). One of the bases. No evidence of intraparenchymal lung or liver
positive ipsilateral level 2A nodes measured 3 cm in its metastasis was visible on the scan. Ultrasound-guided
greatest dimension and exhibited extracapsular tumor therapeutic-diagnostic thoracentesis was performed,
extension; the remaining positive nodes were negative yielding 400 mL of bloody fluid that showed negative
FIGURE 1. Fluorine 18 fluorodeoxyglucose positron emission tomography (PET)–computed tomography 3 months after definitive treatment
showing no evidence of intraparenchymal lung metastasis.
LeRose and Ramirez. Atypical Metastasis to Pleura. J Oral Maxillofac Surg 2018.LEROSE AND RAMIREZ 3
findings for malignancy by cytopathology. Fluorine 18 skeletal system, and liver at rates of up to 52%, 21%,
FDG PET-CT showed extensive lobulated hypermeta- and 6%, respectively.1,2 Tonsillar cancers exhibit a
bolic pleural tissue bilaterally, suggestive of diffuse unique propensity for spread to the liver, showing a
pleural neoplastic disease, and hypermetabolic hepatic metastasis rate of 22%.2 Pleural metastases,
perimediastinal nodes along the left main bronchus an example of which is described in our report, are
posteriorly and left lower part of the esophagus exceedingly rare in the context of head and neck can-
(Fig 2). No hypermetabolic lesions were detected in cer and so are under-represented in the literature. In a
the head or neck to suggest recurrent local or regional clinical study of 779 patients with untreated tumors of
malignancy or within the lung parenchyma to suggest the head and neck (243 of the oropharynx), Probert
the presence of pulmonary metastasis. The findings of et al1 noted only 4 total instances of pleural metastases,
CT-guided biopsy of the pleural tissue confirmed a final whereas a postmortem review by Kotwall et al9 of 832
diagnosis of metastatic infiltrating SCCa. Because of body specimens with more advanced, terminally staged
the extensiveness of secondary disease, palliative head and neck cancers (87 of the tonsillar region) iden-
care measures were initiated and the patient died of tified 58 such instances. Neither of these reports spec-
disease 2 weeks later. ified whether the cases of pleural metastases identified
were incidences of direct secondary or advanced ter-
tiary spread. Reports by Meyer10 and Rodriguez-
Discussion Panadero et al11 specific to the investigation of pleural
Clinical studies have reported head and neck tumors metastasis observed that if secondary spread to the
as showing overall rates of distant metastasis of up to pleura is to occur, it will most commonly arise from pri-
12%, whereas lesions specific to the oropharynx and mary tumors of the lung, breast, ovary, and stomach.
tonsillar region have shown rates of up to 15.3% and Only 2 of 107 cases of pleural metastases described in
6.7%, respectively.1-3 Distant metastases from head these reports were noted to have originated from pri-
and neck tumors have been shown to generally mary tumors in the head and neck.10,11
present within 2 years after definitive treatment,2,4 In the autopsy review of 52 cases by Meyer,10 the
usually in the context of poor locoregional control of pathogenic pathway of carcinomatous metastases to
the primary lesion.2 In a clinical report of 5,019 the pleura has been well described. Regarding tumors
patients with SCCa of the upper respiratory and diges- that are bronchial in origin, the study found that met-
tive tracts, Merino et al2 showed that only 7.9% of astatic spread to the ipsilateral pleura results from
distant metastases occurred in the absence of local dissemination of pulmonary arterial emboli whereas
recurrence or regional spread above the clavicles. Pri- bilateral pleural metastases arise tertiary to initial
mary tumors of the head and neck are reported to hepatic metastases. There was no evidence of pleural
spread most commonly to secondary sites in the lungs, metastases resulting from lymphatic permeation of the
FIGURE 2. Fluorine 18 fluorodeoxyglucose positron emission tomography (PET)–computed tomography 11 months after definitive treatment
showing extensive bilateral lobulated hypermetabolic pleural tissue suggestive of diffuse pleural neoplastic disease.
LeRose and Ramirez. Atypical Metastasis to Pleura. J Oral Maxillofac Surg 2018.4 ATYPICAL METASTASIS TO PLEURA lung parenchyma, except for peripheral tumors and diagnostic yield was increased to 61% when effusion bronchial carcinomas accompanied by extensive cytopathology was performed in combination with parenchymal and centrifugal peribronchial infiltra- pleural biopsy.12 In our report, initial cytopathology tion. Meyer also found that metastatic pleural involve- findings obtained by thoracentesis were negative for ment arising from distant extrapulmonary primary malignancy; it was not until biopsy of the pleura was tumors usually manifests from tertiary spread of estab- additionally performed that a proper diagnosis of lished hepatic metastases. More recent studies by metastatic SCCa was achieved. Rodriguez-Panadero et al11 and Chernow and Sahn12 Metastatic pleural involvement most commonly have challenged this finding, noting that pleural metas- presents with nonspecific symptoms of dyspnea tases from extrapulmonary primary tumors occurred and cough in the context of substantial weight loss; without hepatic involvement in 29% and 30% of cases, chest pain is noted in only 25% of cases.12 As the respectively; this is evidence that preceding hepatic tumor becomes more widespread across the pleura, metastasis is not essential for pleural dissemination patients exhibit a characteristic triad of cachexia, from tumors of extrapulmonary origin to occur. The peripheral adenopathy, and pleural effusion with presence of vascular permeation at the level of the marked hypoxemia.12 The diagnosis of pleural metas- primary lesion was observed in each of these reported tasis of any carcinomatous tumor tends to be accom- cases,11 however, suggesting that perivascular inva- panied by a terminal prognosis. In their report of sion is necessary for extrapulmonary tumors to patients with metastatic pleural carcinoma, Chernow secondarily metastasize the pleura. In our patient, and Sahn12 observed a mean survival time after diag- bilateral pleural metastasis from an extrapulmonary nosis of 3.1 0.5 months; 52% of patients died within SCCa of the tonsil was observed without preceding he- 1 month, 82% by 6 months, and 95% by 1 year. The patic involvement; it was not specified in the surgical patient in our report died of disease within 2 weeks pathology report whether perivascular invasion of the of his diagnosis. primary tumor was detected. Although our case is consistent in presentation and The report by Meyer10 further explained that the clinical course with the descriptions of pleural metas- development of pleural effusion in the context of tases detailed in the literature, it hardly fits the tradi- carcinomatous pleural metastasis is resultant of tumor tional behavior of distant metastases expected from spread to the mediastinal lymph nodes. This descrip- an SCCa tumor of the head and neck. Recent reports, tion is congruent with the observation that fluid however, have suggested that HPV-positive oropha- outflow from pleural effusions is derived from the lym- ryngeal SCCa tumors often show patterns of distant phatics13 and explains why such effusions do not metastases distinct from those of more convention- develop in cases of pleural involvement by secondary ally described HPV-negative head and neck SCCa tu- sarcomas, which are not usually associated with mors. Although associated with superior lymphatic metastases.10 Our report agrees with this locoregional control4-7 and overall survival rates,4-6 finding, as bilateral pleural effusions were detected HPV-positive oropharyngeal SCCa actually shows a with PET-CT evidence of hypermetabolic nodes along higher rate of distant metastasis independent of lo- the left main bronchus and left lower part of the coregional control than does HPV-negative esophagus suggestive of nodal malignancy. Effusions SCCa.4,5,7 Reports by Huang et al4 and Trosman from pleural metastases are most commonly serosan- et al7 showed that distant metastases of HPV- guineous, although they may occasionally contain positive oropharyngeal SCCa were detected without blood,10,12 as in our patient. Bloody effusions result recurrence at the primary tumor site or regional from metastatic infiltration of the deep layers of the lymph nodes at rates of 72% and 85%, respectively. pleura, where occlusion of small venules causes HPV-positive oropharyngeal SCCa also exhibits a vascular engorgement of the superficial pleural layer greater propensity to metastasize to multiple organs and hemorrhage through the endothelial surfaces and distant sites (eg, skin; brain; skeletal muscle; kid- into the thoracic space.10 As shown in this report, cy- ney; pancreatic tail; and nonregional axillary, pericar- topathology studies of pleural effusion aspirates dial, mediastinal, and intra-abdominal lymph nodes) cannot be consistently relied on to rule out the pres- that are atypical for more traditionally described ence of pleural malignancy. The report by Meyer HPV-negative SCCa.4-7 Of particular interest to our showed only 2 of 14 malignant pleural effusions con- report is the finding of Trosman et al of 2 cases in taining cellular material suggestive of neoplasm; in which HPV-positive oropharyngeal SCCa metastasized the remainder of cases, such evidence was scant or secondarily to the pleura. Studies have shown that absent. Similar findings were observed in the study HPV-positive oropharyngeal SCCa may present with of Chernow and Sahn,12 which reported cytopathol- distant metastases at longer intervals after definitive ogy results positive for malignancy in only 25% of effu- treatment than does HPV-negative SCCa.4-7 Huang sions related to pleural metastases. This true-positive et al4 reported that almost all HPV-negative
LEROSE AND RAMIREZ 5
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